Bicyclic compounds and compostions as PDF inhibitors

ABSTRACT

This invention is directed to novel bicyclic compounds, to the uses of these compounds in various medicinal applications, including treating disorders amenable to treatment by peptidyl deformylase inhibitors such as treatment of bacterial infections, and to pharmaceutical compositions comprising these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 60/491,765, filed 31 Jul. 2003. The fulldisclosure of this application is incorporated herein by reference inits entirety and for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to novel bicyclic compounds, to the uses ofthese compounds in various medicinal applications, including treatingdisorders amenable to treatment by peptide deformylase inhibitors suchas treatment of bacterial infections, and to pharmaceutical compositionscomprising of these compounds.

2. Background

Treatment of microbial infection in host organisms requires an effectivemeans to kill the microbe while doing as little harm to the host aspossible. Accordingly, agents that target characteristics unique to apathology-causing microorganism are desirable for treatment. Penicillinis an extremely well known example of such an agent. Penicillin acts byinhibiting biosynthesis of bacterial cell walls. Since mammalian cellsdo not require cell walls for survival, administration of penicillin toa human infected with bacteria may kill the bacteria without killinghuman cells. However, the use of antibiotics and antimicrobials has alsoresulted in increased resistance to these agents. As bacteria becomeresistant to older, more widely used antimicrobial agents, newantimicrobials must be developed in order to provide effectivetreatments for human and non-human animals suffering from microbialinfection.

Peptide deformylase is a metallopeptidase found in prokaryotic organismssuch as bacteria. Protein synthesis in prokaryotic organisms begins withN-formyl methionine (fMet). After initiation of protein synthesis, theformyl group is removed by the enzyme peptide deformylase (PDF); thisactivity is essential for maturation of proteins. It has been shown thatPDF is required for bacterial growth (Chang et al., J. Bacteriol., Vol.171, pp. 4071-4072 (1989); Meinnel et al., J. Bacteriol., Vol. 176, No.23, pp. 7387-7390 (1994); Mazel et al., EMBO J., Vol. 13, No. 4, pp.914-23 (1994)). Since protein synthesis in eukaryotic organisms does notdepend on fMet for initiation, agents that inhibit PDF are attractivecandidates for development of new antimicrobial and antibacterial drugs.Prokaryotic organisms, including disease-causing prokaryotes, aredescribed in Balows A, Truper H G, Dworkin M, Harder W and Schleifer K-H(eds.), “The Prokaryotes”, 2nd ed., New York: Springer-Verlag Q. (1992);and Holt J G (Editor-in-chief), “Bergey & Apos, S., Manual of SystematicBacteriology”, Vols. 1-4, Baltimore: Williams & Wilkins (1982, 1986,1989).

PDF is part of the metalloproteinase superfamily. While PDF shares manyof the features that characterize metalloproteinases, PDF differs fromother members of the superfamily in its secondary/tertiary structure andthe metal ions that are coordinated in the active site.Metalloproteinases are critical to many aspects of normal metabolism.The class known as matrix metalloproteinases (MMPs) are involved intissue remodeling, such as degradation of the extracellular matrix.These enzymes are believed to play a role in normal or beneficialbiological events such as the formation of the corpus luteum duringpregnancy (see Liu et al., Endocrinology, Vol. 140, No. 11, pp.5330-5338 (1999)), wound healing (Yamagiwa et al., Bone, Vol. 25, No. 2,pp. 197-203 (1999)), and bone growth in healthy children (Bord et al.,Bone, Vol. 23, No. 1, pp. 7-12 (1998)). Disorders involvingmetalloproteinases have been implicated in several diseases such ascancer, arthritis and autoimmune diseases. Because of the importance ofMMPs in normal physiological processes, it would be preferable todevelop agents that inhibit PDF, a metalloproteinase present only inprokaryotes, while avoiding significant inhibition of MMPs.Alternatively, PDF inhibitors that also inhibit MMPs may be of use wherethe therapeutic benefits of inhibiting PDF outweighs the risk of sideeffects from MMP inhibition.

While a wide variety of compounds have been developed as candidateinhibitors of MMPs and other metalloproteinases, research on inhibitorsof PDF is much less extensive. In view of the importance of identifyingnew antibiotics to treat bacteria resistant to existing antibiotics, itis desirable to develop novel inhibitors of PDF for evaluation and useas antibacterial and antimicrobial agents. The present inventionfulfills this need.

SUMMARY OF THE INVENTION

This application relates to compounds of Formula I:

in which:

-   -   n is 1, 2 or 3;    -   Z is selected from —CH₂—, —CH₂CH₂—, —S—, —S(O)—, —S(O)₂— and        —NR₄—; wherein R₄ is selected from hydrogen, hydroxy, halo and        C₁₋₄alkyl;    -   R₁ is selected from hydrogen, C₁₋₆alkyl, —XC(O)NR₅OR₆, —XNR₅COR₆        and —XC(O)NR₅R₆; wherein X is selected from a bond,        C₁₋₆alkylene, C₂₋₆alkenylene and C₂₋₆alkynylene; wherein X can        be optionally substituted with halo, hydroxy and cyano; R₅ is        selected from hydrogen, hydroxy and C₁₋₄alkyl; and R₆ is        selected from hydrogen and C₁₋₄alkyl;    -   R₂ is selected from hydrogen, C₁₋₁₂alkyl, C₂₋₁₂alkenyl,        C₂l2alkynyl, halo-substituted-C₁₋₁₂alkyl, —XOR₅, —XOR₇,        —XC(O)OR₅, —XOC(O)R₅, —XC(O)NR₅R₆, —XC(O)NR₅R₇, —XC(O)NR₅OR₆,        —XR₇, —XCHR₇R₇, —XC(O)R₆, —XOXOR₆, —XOXOR₇, —XC(O)R₇, —XC≡N,        —XC(O)XR₇, —XOXR₇, —XC(O)NR₅XR₇ and —XC(O)NR₅XNR₅R₆; wherein X,        R₅ and R₆ are as described above and R₇ is selected from        C₃₋₁₀cycloalkyl, C₅₋₈heterocycloalkyl, C₆₋₁₀aryl and        C₅₋₈heteroaryl; wherein any cycloalkyl, heterocycloalkyl, aryl        or heteroaryl of R₇ can be optionally substituted by one to        three radicals selected from halo, C₁₋₄alkyl, C₁₋₄alkoxy, cyano,        halo-substituted-C₁₋₄alkyl and —XC(O)OR₅; wherein X and R₅ are        as described above; with the proviso that R₁ and R₂ cannot both        be hydrogen; with the proviso that when R₂ is not hydrogen when        R₁ is —CH₂C(O)NHOH; with the proviso that R₁ and R₂ are both not        hydrogen;    -   R₃ is selected from hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy,        halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy; and        the N-oxide derivatives, prodrug derivatives, individual isomers        and mixtures of isomers thereof; and the pharmaceutically        acceptable salts and solvates (e.g. hydrates) of such compounds.

A second aspect of the invention is a pharmaceutical composition whichcontains a compound of Formula I or an N-oxide derivative, individualisomer or mixture of isomers thereof, or a pharmaceutically acceptablesalt thereof, in admixture with one or more suitable excipients.

A third aspect of the invention is a method for treating a disease in ananimal in which inhibition of PDF activity can prevent, inhibit orameliorate the pathology and/or symptomology of the disease, whichmethod comprises administering to the animal a therapeutically effectiveamount of a compound of Formula I or a N-oxide derivative, individualisomer or mixture of isomers thereof; or a pharmaceutically acceptablesalt thereof.

A fourth aspect of the invention is the use of a compound of Formula Iin the manufacture of a medicament for treating a disease in an animalin which PDF activity contributes to the pathology and/or symptomologyof the disease.

A fifth aspect of the invention is a process for preparing compounds ofFormula I and the N-oxide derivatives, prodrug derivatives, protectedderivatives, individual isomers and mixtures of isomers thereof; and thepharmaceutically acceptable salts thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides compounds that are useful in the treatment and/orprevention of diseases or disorders mediated by PDF activity. Alsoprovided are methods for treating such diseases or disorders.

DEFINITIONS

In this specification, unless otherwise defined:

“Alkyl” as a group and as a structural element of other groups, forexample halo-substituted-alkyl, alkoxy, acyl, alkylthio, alkylsulfonyland alkylsulfinyl, can be either straight-chained or branched. “Alkenyl”as a group and as a structural element of other groups contains one ormore carbon-carbon double bonds, and can be either straight-chain, orbranched. Any double bonds can be in the cis- or trans-configuration. Apreferred alkenyl group is vinyl. “Alkynyl” as a group and as structuralelement of other groups and compounds contains at least one C≡C triplebond and can also contain one or more C═C double bonds, and can, so faras possible, be either straight-chain or branched. A preferred alkynylgroup is propargyl. Any cycloalkyl group, alone or as a structuralelement of other groups can contain from 3 to 8 carbon atoms, preferablyfrom 3 to 6 carbon atoms. “Alkylene” and “alkenylene” are divalentradicals derived from “alkyl” and “alkenyl” groups, respectively.

“Aryl” means a monocyclic or fused bicyclic aromatic ring assemblycontaining six to ten ring carbon atoms. For example, C₆₋₁₂aryl can bephenyl, biphenyl or naphthyl, preferably phenyl. “Arylene” means adivalent radical derived from an aryl group. For example, arylene asused in this application can be phenylene, biphenylene or naphthylene,preferably phenylene, more preferably 1,4-phenylene.

“Bicycloaryl” means a bicyclic ring assembly containing the number ofring carbon atoms indicated, wherein the rings are linked by a singlebond or fused and at least one of the rings comprising the assembly isaromatic. For example bicycloaryl includes naphthyl, biphenyl, and thelike. “Tricycloaryl” means a tri-cyclic ring assembly containing thenumber of ring carbon atoms indicated, wherein the rings are fused andat least one of the rings comprising the assembly is aromatic. Forexample, tricycloaryl includes anthracenyl and the like.“Bicycloarylene” is a divalent radical derived from a bicycloaryl group.“Heterotricycloaryl” means tricycloaryl as defined in this applicationprovided that one or more carbon atoms is replaced by a heteroatommoiety selected from —N═, —NR—, —O—, —S—, —S(O)— and —S(O)₂— (wherein Rof —NR— is hydrogen or C₁₋₄alkyl). “Heterotricycloarylene” is a divalentradical derived from a heterotricycloaryl group and includes, forexample, 5,7-dihydro-oxazolo[4,5-f]isoindol-6-ylene. “Heterobicycloaryl”means bicycloaryl as defined in this application provided that one ormore carbon atoms is replaced by a heteroatom moiety selected from —N═,—NR—, —O—, —S—, —S(O)— and —S(O)₂— (wherein R of —NR— is hydrogen orC₁₋₄alkyl). For example, C₈₋₁₀heterobicycloarylene, as used to describeY of Formula I, includes benzooxazol-2-yl, benzothiazol-2-yl, and thelike.

“Halo” or “halogen” means F, Cl, Br or I, preferably F or Cl.Halo-substituted alkyl groups and compounds can be partially halogenatedor perhalogenated, whereby in the case of multiple halogenation, thehalogen substituents can be identical or different. A preferredperhalogenated alkyl group is for example trifluoromethyl.

“Heteroaryl” means aryl, as defined in this application, provided thatone or more of the ring carbon atoms indicated are replaced by a heteroatom moiety selected from N, O or S, and each ring is comprised of 5 to6 ring atoms, unless otherwise stated. For example, heteroaryl as usedin this application includes thiophenyl, pyridinyl, furanyl, isoxazolyl,benzoxazolyl or benzo[1,3]dioxolyl, preferably thiophenyl, furanyl orpyridinyl. “Heteroarylene” means heteroaryl, as defined in thisapplication, provided that the ring assembly comprises a divalentradical.

“Protecting group” refers to a chemical group that exhibits thefollowing characteristics: 1) reacts selectively with the desiredfunctionality in good yield to give a protected substrate that is stableto the projected reactions for which protection is desired; 2) isselectively removable from the protected substrate to yield the desiredfunctionality; and 3) is removable in good yield by reagents compatiblewith the other functional group (s) present or generated in suchprojected reactions. Examples of suitable protecting groups may be foundin Greene et al., “Protective Groups in Organic Synthesis”, 2nd Ed.,John Wiley & Sons, Inc., New York (1991). Preferred amino protectinggroups include, but are not limited to, benzyloxycarbonyl (CBz),t-butyl-oxycarbonyl (Boc), T-butyldimethylsilyl (TBDMS),9-fluorenylmethyl-oxycarbonyl (Fmoc), or suitable photolabile protectinggroups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl,pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzyl,5-bromo-7-nitroindolinyl, and the like. Preferred hydroxy protectinggroups include Fmoc, TBDMS, photolabile protecting groups (such asnitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), andMem (methoxy ethoxy methyl ether). Particularly preferred protectinggroups include NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM(4-nitrophenethyloxy-methyloxycarbonyl).

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compounds that are useful for treating orpreventing diseases or disorders that are mediated by PDF activity. Inone embodiment, for compounds are of Formula I: n is 1 or 2; Z isselected from —CH₂—, —CH₂CH₂— and —S—; R₁ is selected from hydrogen,—XC(O)NR₅OR₆ and —XNR₅COR₆; wherein X is selected from a bond,C₁₋₆alkylene, C₂₋₆alkenylene and C₂₋₆alkynylene; wherein X can beoptionally substituted with hydroxy; R₅ is selected from hydrogen,hydroxy and C₁₋₄alkyl; and R₆ is selected from hydrogen and C₁₋₄alkyl;R₂ is selected from hydrogen, C₁₋₁₂alkyl, C₂₋₁₂alkenyl,halo-substituted-C₁₋₁₂alkyl, —XOR₅, —XOR₇, —XC(O)OR₅, —XOC(O)R₅,—XC(O)NR₅R₆, —XC(O)NR₅R₇, —XC(O)NR₅OR₆, —XR₇, —XCHR₇R₇, —XC(O)R₆,—XOXOR₆, —XOXOR₇, —XOXR₇, —XC(O)R₇, —XC≡N, —XC(O)NR₅XR₇ and—XC(O)NR₅XNR₅R₆; wherein X, R₅ and R₆ are as described above and R₇ isselected from C₃₋₁₀cycloalkyl, C₅₋₈heterocycloalkyl, C₆₋₁₀aryl andC₅₋₈heteroaryl; wherein any cycloalkyl, heterocycloalkyl, aryl orheteroaryl of R₇ can be optionally substituted by one to three radicalsselected from halo, C₁₋₄alkyl, C₁₋₄alkoxy, cyano and —XC(O)OR₅; whereinX and R₅ are as described above; and R₃ is selected from hydrogen andhalo.

In another embodiment, R₁ is selected from hydrogen, —XC(O)NR₅OR₆ and—XNR₅COR₆; wherein X is selected from a bond, C₁₋₆alkylene,C₂₋₆alkenylene and C₂₋₆alkynylene; wherein X can be optionallysubstituted with hydroxy; R₅ is selected from hydrogen, hydroxy andC₁₋₄alkyl; and R₆ is selected from hydrogen and C₁₋₄alkyl; R₂ isselected from hydrogen, C₁₋₁₂alkyl, C₂₋₁₂alkenyl,halo-substituted-C₁₋₁₂alkyl, —XOR₅, —XOR₇, —XC(O)OR₅, —XOC(O)R₅,—XC(O)NR₅R₆, —XC(O)NR₅R₇, —XC(O)NR₅OR₆, —XR₇, —XCHR₇R₇, —XC(O)R₆,—XOXOR₆, —XOXOR₇, —XOXR₇, —XC(O)R₇, —XC≡N, —XC(O)NR₅XR₇ and—XC(O)NR₅XNR₅R₆; wherein X, R₅ and R₆ are as described above and R₇ isselected from C₃₋₁₀cycloalkyl, C₅₋₈heterocycloalkyl, C₆₋₁₀aryl andC₅₋₈heteroaryl; wherein any cycloalkyl, heterocycloalkyl, aryl orheteroaryl of R₇ can be optionally substituted by one to three radicalsselected from halo, C₁₋₄alkyl, C₁₋₄alkoxy, cyano and —XC(O)OR₅; whereinX and R₅ are as described above; and R₃ is selected from hydrogen andhalo.

In another embodiment, Z is —S—.

In a further embodiment, R₁ is selected from hydrogen,methoxy-carbamoyl-methyl, hydroxy-carbamoyl-methyl,hydroxy-carbamoyl-hydroxy-methyl, (formyl-hydroxy-amino)-methyl and(acetyl-hydroxy-amino)-methyl.

In a further embodiment, R₂ is selected from hydrogen, carbamoyl-methyl,cyano-methyl, methyl, cyclopropyl-methyl, benzyl,hydroxy-carbamoyl-methyl, 2-methoxy-ethyl, 3,3,3-trifluoro-propyl,3-methyl-butyl, 4-methyl-pentyl, pentyl, cyclobutyl-methyl,1-methyl-2-oxo-2-phenyl-ethyl, cyclohexyl-methyl, cyclohexyl-ethyl,3,3-dimethyl-2-oxo-butyl, but-3-enyl, pyridin-2-yl-carbamoyl-methyl,(3,4-difluoro-phenylcarbamoyl)-methyl,(2,6-diethyl-phenylcarbamoyl)-methyl,[1-(4-fluoro-phenyl)-ethyl-carbamoyl]-methyl,2-oxo-2-pyrrolidin-1-yl-ethyl, (2,5-difluoro-benzylcarbamoyl)-methyl,propyl-carbamoyl-methyl, (2-dimethylamino-ethylcarbamoyl)-methyl, butyl,phenethyl, formyl-hydroxy-amino, 1-carbamoyl-ethyl,2-[1,3]dioxolan-2-yl-ethyl, tetrahydro-pyran-2-yl-methyl,2-fluoro-benzyl, 4-fluoro-benzyl, 2,4-difluoro-benzyl, 2-cyano-benzyl,3-cyano-benzyl, 4-cyano-benzyl, 3-methoxy-benzyl,2-(4-cyano-phenyl)-2-oxo-ethyl, carboxy-methyl,2-(4-carboxy-methyl-ester-phenyl)-2-oxo-ethyl,pyridin-3-yl-carbamoyl-methyl, 3,7-dimethyl-octyl, 2-oxo-butyl,2-(2-methoxy-ethoxy)-ethyl, 3,3-diphenyl-propyl, ethyl, 2-ethyl-butyl,3-fluoro-propyl, 3-benzyloxy-propyl, 4-phenoxy-butyl,2-(3-methoxy-phenyl)-2-oxo-ethyl, 2-(4-methoxy-phenyl)-2-oxo-ethyl,4-carboxy-benzyl, 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl, nonyl,3-methoxy-carbonyl-propyl, 4-cyano-butyl, 3-methyl-but-2-enyl,phenyl-propyl, ethoxy-ethyl, 4-methyl-pent-3-enyl, phenoxy-ethyl,4-methoxycarbonyl-butyl, 4-acetoxy-butyl, 4-propionyloxy-butyl andhexyl.

Preferred compounds of the invention are shown in table 1, infra.

The invention provides forms of the compound that have the hydroxyl oramine group present in a protected form; these function as prodrugs.Prodrugs are compounds that are converted into an active drug form afteradministration, through one or more chemical or biochemicaltransformations. The antibacterial potency of compounds that are potentinhibitors of the PDF enzyme in vitro, but penetrate the cell wallpoorly, can be improved by their use in the form of a prodrug that isconverted to the parent molecule after passing through the cell wall.Forms of the compounds of the present invention that are readilyconverted into the claimed compound under physiological conditions areprodrugs of the claimed compounds and are within the scope of thepresent invention. Examples of prodrugs include forms where a hydroxylgroup is acylated to form a relatively labile ester such as an acetateester, and forms where an amine group is acylated with the carboxylategroup of glycine or an L-amino acid such as serine, forming an amidebond that is particularly susceptible to hydrolysis by common metabolicenzymes.

Compounds of Formula I can exist in free form or in salt form, e.g.addition salts with inorganic or organic acids. Where hydroxyl groupsare present, these groups can also be present in salt form, e.g. anammonium salt or salts with metals such as lithium, sodium, potassium,calcium, zinc or magnesium, or a mixture thereof. Compounds of Formula Iand their salts in hydrate or solvate form are also part of theinvention.

When the compounds of Formula I have asymmetric centers in the molecule,various optical isomers are obtained. The present invention alsoencompasses enantiomers, racemates, diastereoisomers and mixturesthereof. Moreover, when the compounds of Formula I include geometricisomers, the present invention embraces cis-compounds, trans-compoundsand mixtures thereof. Similar considerations apply in relation tostarting materials exhibiting asymmetric carbon atoms or unsaturatedbonds as mentioned above.

Methods for Preparing Antibacterial Compounds

The present invention also includes processes for the preparation ofantibacterial compounds of the invention. In the reactions described, itcan be necessary to protect reactive functional groups, for examplehydroxy, amino, imino, thio or carboxy groups, where these are desiredin the final product, to avoid their unwanted participation in thereactions. Conventional protecting groups can be used in accordance withstandard practice, for example, see T. W. Greene and P. G. M. Wuts in“Protective Groups in Organic Chemistry”, John Wiley and Sons, 1991.

Compounds of Formula I can be prepared by proceeding as in the followingreaction scheme 1:

in which n, Z, R₁, R₂ and R₃ are as defined for Formula I, above. Y is ahalogen, or the like. The reaction can proceed in the presence of asuitable base (e.g., NaH, LDA or the like) in a suitable solvent (e.g.,DMF, THF, DMSO or the like) at a temperature of about 25° C. and cantake up to 12 hours to complete.

Additional Processes for Preparing Compounds of the Invention:

A compound of the invention can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the invention can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Alternatively, the salt forms of the compounds of the inventioncan be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the invention canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the invention in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the invention in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Compounds of the invention in unoxidized form can be prepared fromN-oxides of compounds of the invention by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of the invention can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al., (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of the invention with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of the invention can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T W. Greene, “Protecting Groupsin Organic Chemistry”, 3^(rd) edition, John Wiley and Sons, Inc., 1999.

Compounds of the present invention can be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofliranor methanol.

Compounds of the invention can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomers. While resolution of enantiomers can be carried outusing covalent diastereomeric derivatives of the compounds of theinvention, dissociable complexes are preferred (e.g., crystallinediastereomeric salts). Diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and can be readily separated by taking advantage of thesedissimilarities. The diastereomers can be separated by chromatography,or preferable, by separation/resolution techniques based upondifferences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom the their racemic mixture can be found in Jean Jacques, AndreCollet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, JohnWiley And Sons, Inc., 1981.

In summary, the compounds of Formula I can be made by a process, whichinvolves:

-   -   (b) (a) reaction scheme 1; or    -   (b) optionally converting a compound of the invention into a        pharmaceutically acceptable salt;    -   (c) optionally converting a salt form of a compound of the        invention to a non-salt form;    -   (d) optionally converting an unoxidized form of a compound of        the invention into a pharmaceutically acceptable N-oxide;    -   (e) optionally converting an N-oxide form of a compound of the        invention to its unoxidized form;    -   (f) optionally resolving an individual isomer of a compound of        the invention from a mixture of isomers;    -   (g) optionally converting a non-derivatized compound of the        invention into a pharmaceutically acceptable prodrug derivative;        and    -   (h) optionally converting a prodrug derivative of a compound of        the invention to its non-derivatized form.

Insofar as the production of the starting materials is not particularlydescribed, the compounds are known or can be prepared analogously tomethods known in the art or as disclosed in the Examples hereinafter.

One of skill in the art will appreciate that the above transformationsare only representative of methods for preparation of the compounds ofthe present invention, and that other well known methods can similarlybe used.

EXAMPLES

The following examples provide detailed descriptions of the preparationof representative compounds and are offered to illustrate, but not tolimit the present invention.

Example 12-(2-Hydroxycarbamoylmethyl-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-propionamide

To a solution of (3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-aceticacid ethyl ester (0.59 mmol) in 1 mL of anhydrous DMF is added NaH (60%in mineral oil) (0.77 mmol) and the mixture is stirred at roomtemperature for 20 minutes. 2-Bromo propionamide is then added and thereaction is stirred at room temperature for 12 hours. The solvent isevaporated and the crude[4-(1-carbamoyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl]-aceticacid ethyl ester is used in the next step without further purification.

The[4-(1-carbamoyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl]-aceticacid ethyl ester obtained in the previous step is dissolved in 500 μL ofMeOH and 500 μL of DMF and treated with 400 μL of LiOH (3M). Thereaction is stirred at room temperature for 12 hours and then thesolvent is evaporated. The resulting mixture is diluted with EtOAc andwashed with HCl (1M). The organic layer is dried over Na₂SO₄, filteredand the solvent evaporated. The crude[4-(1-carbamoyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl]-aceticacid is used in the next step without further purification.

The crude[4-(1-carbamoyl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl]-aceticacid is dissolved in 1 mL of anhydrous THF and EtCOCl (0.71 mmol) isadded at 0 ° C. followed by N-methylmorpholine (0.76 mmol). The reactionmixture is stirred at 0 ° C. for 10 minutes. Freshly prepared NH₂OH (1Min MeOH) (0.88 mmol) is added and the reaction stirred at roomtemperature for 15 minutes. After evaporation of the solvent the final2-(2-hydroxycarbamoylmethyl-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-propionamideis obtained by preparative LC/MS (in the absence of TFA) using 1 to 99%ACN as gradient. ¹H NMR (400 MHz, MeOD): δ 7.28 (m, 1H), 7.18 (m, 1H),7.04 (m, 1H), 6.96 (m, 1H), 5.26 (m, 1H), 3.73 (m, 1H), 2.5 (m, 1H),2.19 (m, 1H), 1.26 (m, 3H). MS: (ES⁺): 332.2 [M+23].

Example 22-(2-Hydroxycarbamoylmethyl-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-N-(pyridin-2-yl)acetamide

To a solution of LDA (2M) in THF (3.26 mmol) in 2 mL of anhydrous THF at0° C. and under nitrogen, a solution of(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid ethyl ester(1.62 mmol) in 4 mL of dry THF is added dropwise. The temperature of thereaction mixture is held at room temperature for 2 hours and thendropped to −78° C. A solution of 2-bromo acetic acid (1.64 mmol) in 2 mLof anhydrous THF is added and the temperature of the reaction is slowlylet to rise to room temperature. HCl (1M) is added to reach pH=1. Ethylether is added and the phases are separated. The organic phase is driedon Na₂SO₄, the drying agent is filtered and the solvent evaporated. Thecrude product is purified by automated column chromatography(hexane/EtOAc) to give the product ethyl2-(3,4-dihydro-4-(carboxymetyl)-3-oxo-2H-benzo[b][1,4]thiazin-2-yl)acetate.Yield: 50%. ¹H NMR (400 MHz, CDCl₃): δ 9.07 (bs, 1H), 7.38 (d, J=7.6 Hz,1H), 7.27 (t, J=7.6 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 6.93 (d, J=7.6 Hz,1H), 4.69 (dd, 2H), 4.18 (dd, 2H), 3.99 (t, J=6.4 Hz, 1H), 3.04 (dd,J₁=6.4 Hz, J₂=16.8 Hz, 1H), 2.58 (dd, 1H), 1.26 (m, 3H).

To a solution of2-(3,4-dihydro-4-(carboxymetyl)-3-oxo-2H-benzo[b][1,4]thiazin-2-yl)acetate(0.35 mmol) in 1 mL of anhydrous DMF is added 2-amino pyridine (0.42mmol), DIEA (0.42 mmol) and HATU (0.42 mmol). The reaction mixture isthen stirred for 4 hours. After the evaporation of the solvent the2-(2-carboethoxymethyl-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-N-(pyridin-2-yl)acetamideis obtained by automated column chromatography (hexane/EtOAc). Yield:40%.

The2-(2-carboethoxymethyl-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-N-(pyridin-2-yl)acetamideobtained in the previous step is dissolved in 1 mL of MeOH and treatedwith 430 μL of LiOH (3M). The reaction is stirred at room temperaturefor 12 hours and then the solvent is evaporated. The resulting mixtureis diluted with EtOAc and washed with HCl (1M). The organic layer isdried over Na₂SO₄, filtered and the solvent evaporated.

The crude2-(2-carboxymethyl-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-N-(pyridin-2-yl)acetamideis dissolved in 0.5 mL of anhydrous ethyl ether and EtCOCl (0.043 mmol)is added at 0° C. followed by N-methylmorpholine (0.044 mmol). Thereaction mixture is stirred at 0° C. for 10 minutes. Freshly preparedNH₂OH (1M in MeOH) (0.054 mmol) is added and the reaction stirred atroom temperature for 15 minutes. The final2-(2-hydroxycarbamoylmethyl-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-N-(pyridin-2-yl)acetamideis obtained by preparative LC/MS (in the absence of TFA) using 1 to 99%ACN as gradient. ¹H NMR (400 MHz, MeOD) δ 8.23 (d, 1H, J=8.0 Hz), 7.90(t, 1H, J=8.0 Hz), 7.80 (d, 1H, J=8.0 Hz), 7.32 (d, 1H, J=9.0 Hz), 7.20(m, 2H), 7.05 (d, 1H, J=9.0 Hz), 7.01 (t, 1H, J=8.0 Hz), 4.77 (s, 2H),3.91 dd, 1H, J=6.6 Hz, J=8.8 Hz), 2.65 (dd, 1H, J=6.6 Hz, J=14.4 Hz),2.28 (dd, 1H, J=8.8 Hz, J=14.4 Hz). MS: (ES⁺): 373.20 [M+1].

Example 32-(8-Bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-N-hydroxy-acetamide

A solution of 2-chloro-1,3-dinitro-benzene (10 mmol) in 30 mL of DMF iscooled down to 0° C. 2-Mercapto-succinic acid bis-(3-methyl-butyl)ester(11 mmol) is added as one portion. After the addition, Et₃N (12 mmol) isadded dropwise into the mixture while keeping the temperature at 0° C.After stirring at 0° C. for 2 hours, the mixture is poured into water(300 mL) and is extracted with EtOAc (3×50 mL). The organic layers arecombined and washed with brined and dried over MgSO₄. After filteringoff the drying agent, the filtrate is concentrated and purified by flashcolumn chromatography (silica gel, 0˜25% EtOAc/hexane) to provide thedesired product 2-(2,6-dinitro-phenylsulfanyl)-succinic acidbis-(3-methyl-butyl)ester as dark red oil. Yield: 59%. MS: (ES⁺): 457[M+1].

Iron powder (108.7 mmol) is added to a solution of2-(2,6-dinitro-phenylsulfanyl)-succinic acid bis-(3-methyl-butyl)ester(4.35 mmol) in 40 mL EtOH, followed by the addition of 8 mL of water and4 mL of HCl (1M). The mixture is heated to 90° C. and stirred for 3hours. After filtering off the iron, the mixture is cooled down to roomtemperature and concentrated. The residue is purified by flash columnchromatography. (silica gel, 0˜30% EtOAc/hexane) to provide the desiredproduct (8-amino-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-aceticacid 3-methyl-butyl ester as off white solid. Yield: 80%. MS: (ES⁺):309[M+1].

To a solution of(8-amino-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid3-methyl-butyl ester (0.49 mmol) in 3 mL of acetonitrile,tert-butylnitrite is added (0.73 mmol) followed by CuBr₂ (0.59 mmol) at0° C. After the mixture is stirred at 0° C. for 30 minutes, it is pouredinto 10 mL of HCl (1M) solution and extracted with EtOAc (20 mL). Theorganic layer is collected and washed with brine and dried over MgSO₄.After filtering off the drying agent, the filtrate is concentrated andpurified by flash column chromatography (silica gel, 0˜15% EtOAc/hexane)to provide the desired product(8-bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid3-methyl-butyl ester as white solid. Yield: 24%. MS: (ES⁺): 372 [M+1].

To a solution of(8-bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid3-methyl-butyl ester (0.12 mmol) obtained from the previous reaction in2 mL of EtOH is added NaOH (1N) (0.24 mmol). After the mixture isstirred at room temperature for 2 hours, 0.3 mL of HCl (1M) is added.The mixture is then extracted with EtOAc (3×5 mL). The organic layersare combined, concentrated and redissolved in 2 mL of anhydrous Et₂O.Following a similar procedure as described in Example 1, the8-bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid isconverted to the title compound2-(8-bromo-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-N-hydroxy-acetamideand purified by preparative thin layer chromatography. ¹H NMR (400 MHz,MeOD) δ 7.18 (d, 1H, J=8.0 Hz), 6.70 (t, 1H, J=8.0 Hz), 6.85 (d, 1H,J=8.0 Hz), 3.88 (dd, 1H, J=9.0 Hz, J=5.6 Hz), 2.66 (dd, 1H, J=5.6 Hz,J=14.9 Hz), 2.25 (dd, 1H, J=9.0 Hz, J=14.9 Hz). MS: (ES⁺): 317.10 [M+1].

Example 42,N-Dihydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetamide

To a solution of 4H-benzo[1,4]thiazin-3-one (6.06 mmol) in 30 mL ofanhydrous THF at −78° C. is added freshly prepared LDA (13.9 mmol)dropwise. After the mixture is stirred at −78° C. for 30 minutes, it iswarmed up to 0° C. for 30 minutes and cooled down to −78° C. again. Theresulting mixture is then slowly transferred using a double-ended needleinto a solution of ethyl glyoxalate (18.3 mmol, 50% in toluene) in 10 mLof anhydrous THF kept at −78° C. After the addition, the mixture isallowed to slowly warm up to 0° C. and to stir for 3 hours. 2 mL of amixture of EtOH and water (1:1) is added to quench the reaction and themixture is poured into a saturated aqueous solution of NH₄Cl (50 mL).After the extraction with EtOAc (3×40 mL), the organic layers arecombined and washed with brine and dried over MgSO₄. After filtering offthe drying agent, the solution is concentrated and purified by flashcolumn chromatography (silica gel, 0˜2% EtOH/CH₂Cl₂) to provide thedesired producthydroxy-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid ethylester as a white solid. Yield: 32%. MS: (ES⁺): 268 [M+1].

To a solution ofhydroxy-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid ethylester (1.12 mmol) in 5 mL of EtOH is added NaOH (1N) (2.24 mmol) and themixture is stirred at room temperature for 1 hour. Water (20 ml) isadded into the mixture followed by extraction (EtOAc, 3×10 mL). Theaqueous layer is then treated with HCl (1N) (2.5 mL) and extracted withEtOAc (3×30 mL). The combined extracts are washed with brine and driedover MgSO₄. After filtering off the drying agent, the solution isconcentrated to provide the crude producthydroxy-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid as aoff white solid. Yield: 76%. MS: (ES⁺): 240 [M+1].

A mixture ofhydroxy-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetic acid (0.13mmol) and p-TSA (1 mg) in 1.5 mL of 2,2-dimethoxypropane is stirred atroom temperature for 16 hours. Solvent is removed under vacuum and theresidue is treated with a saturated aqueous solution of NaHCO₃ (2 mL).The resulted mixture is extracted with EtOAc (3×5 mL). The organiclayers are combined and concentrated to provide the crude2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-4H-benzo[1,4]thiazin-3-onewhich was used directly for next step without further purification.Yield: 31%

The crude2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-yl)-4H-benzo[1,4]thiazin-3-one(0.036 mmol) is dissolved in 0.5 mL of THF and 0.5 mL of NH₂OH (1N inMeOH) is added to the mixture. After the addition, the mixture isstirred at 60° C. for 3 hours. The solvent is then removed under vacuumand the residue is purified by preparative thin layer chromatography(silica gel, 10% MeOH/CH₂Cl₂) to provide the title compound2,N-dihydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetamide.Yield: 70%. ¹H NMR (400 MHz, MeOD) δ 7.30 (dd, 1H, J=1.29 Hz, J=8.0 Hz),7.18, (dt, 1H, J=1.3 Hz, J=8.0 Hz), 7.01 (dt, 1H, J=1.3 Hz, J=8.0 Hz),6.95 (dd, 1H, J=1.3 Hz, J=8.0 Hz), 4.74 (d, 1H, J=3.80), 3.97 (d, 1H,J=3.8). MS: (ES⁺): 255.1[M+1].

Example 5N-Hydroxy-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-ylmethyl)-formamide

4H-Benzo[1,4]thiazin-3-one (165 mmol) is dissolved in 60 mL of CH₂Cl₂and then sulfuryl chloride is added (135 mmol) slowly over a 30 minuteperiod. The mixture is stirred for 12 hours and then the solvent isevaporated. The crude 2-chloro-4H-benzo[1,4]thiazin-3-one is used in thenext step without further purification.

2-Chloro-4H-benzo[1,4]thiazin-3-one (60.5 mmol) is dissolved intriethylphosphite (269 mmol) and the mixture is heated to 100° C. Thecolor gradually changes from pale yellow to orange. After 2 hours theexcess triethylphosphite is removed under vacuum and the product(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-phosphonic acid diethylester is purified by column chromatography (hexane/EtOAc). Yield: 40%.¹H NMR (400 MHz, CDCl₃): δ 7.25 (m, 1H), 7.09 (m, 1H), 6.94 (m, 1H),6.82 (m, 1H), 4.08 (m, 2H), 3.96 (m, 1H), 3.79 (m, 2H), 1.20 (t, 3H),0.95 (t, 3H). MS: (ES⁺): 302.2 [M+1].

(3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-phosphonic acid diethylester (12.2 mmol) is dissolved in 40 mL of anhydrous MeOH andformaldehyde (37%) in water (12.2 mmol) is added to the orange solution.NaOMe (2N in MeOH) (12.2 mmol) is added and the reaction is cooled downto 0° C. The solid that precipitates is filtered to give2-methylene-4H-benzo[1,4]thiazin-3-one. Yield: 72%. ¹H NMR (400 MHz,CDCl₃): δ 9.03 (s, 1H), 7.06 (m, 2H), 6.94 (m, 1H), 6.81 (m, 1H), 6.80(s, 1H), 5.62 (s, 1H). MS: (ES⁺): 178.2 [M+1].

To a solution of 2-methylene-4H-benzo[1,4]thiazin-3-one (5.14 mmol) in10 mL of anhydrous DMF, Et₃N (25.7 mmol) is added followed byO-benzylhydroxylamine hydrochloride (25.7 mmol). The mixture is stirredat 100° C. for 12 hours and then the solvent is evaporated. The crude ispurified by column chromatography (hexane/EtOAc) to give2-(benzyloxyamino-methyl)-4H-benzo[1,4]thiazin-3-one. Yield 58%. ¹H NMR(400 MHz, CDCl₃): δ 8.51 (s, 1H), 7.13 (m, 9H), 6.1 (bs, 1H), 4.64 (s,2H), 3.86 (m, 1H), 3.3 (m, 1H), 2.9 (m, 1H). MS: (ES⁺): 301.2 [M+1].

To a solution of 2-(benzyloxyamino-methyl)-4H-benzo[1,4]thiazin-3-one(2.96 mmol) in 15 mL of formic acid at 0° C., acetic anhydride is added(15.1 mmol) and the reaction is stirred at room temperature overnight.The mixture is diluted with EtOAc and washed with water followed bybrine and NaHCO₃. Purification by column chromatography (hexane/EtOAc)givesN-benzyloxy-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-ylmethyl)-formamide.Yield: 81%. MS: (ES⁺): 329.2 [M+1].

To a solution ofN-benzyloxy-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-ylmethyl)-formamide(0.17 mmol) in EtOH (12 mL) is added Pd/C (10%) (88.5 mg) followed bycyclohexadiene (1.8 mL). The reaction mixture is stirred at roomtemperature for 12 hours and the final productN-hydroxy-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-ylmethyl)-formamideis obtained by preparative LC/MS using 1 to 99% ACN as gradient. ¹H NMR(400 MHz, MeOD): δ 8.48 (s, 0.4H), 7.97 (s, 0.6H), 7.49 (m, 2H), 7.19(m, 2H), 4.03 (m, 2H), 3.5 (dd, 1H). MS: (ES⁺): 239.1[M+1].

Example 62-{2-[(Benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4thiazin-4-yl}-N-propyl-acetamide

To a solution ofN-benzyloxy-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-ylmethyl)-formamide(2.4 mmol), synthesized as described in example 5, in anhydrous DMF isadded NaH (60% in mineral oil) (3.36 mmol) and the mixture is stirred atroom temperature for 30 minutes. Tert-butyl bromoacetate is then addedand the reaction is stirred at room temperature overnight. The solventis evaporated and the crude{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-aceticacid tert-butyl ester is used in the next step without furtherpurification.

The{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-aceticacid tert-butyl ester obtained in the previous step is treated with TFA(2.4 mmol) in 12 mL of formic acid. The reaction is stirred at roomtemperature for 3 hours. The solvent is removed and the mixture ispurified by column chromatography (hexane/EtOAc) yielding{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-aceticacid. Yield: 50%. MS: (ES⁺): 359.2 [M+1].

To a solution of{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-aceticacid (0.13 mmol) in anhydrous DMF, propylamine (0.13 mmol) is addedfollowed by DIEA (0.13 mmol) and HATU (0.13 mmol). The reaction mixtureis stirred overnight and the desired product2-{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-N-propyl-acetamideis obtained and used in the next step without further purification. MS:(ES⁺): 428.2 [M+1].

To a solution of2-{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-N-propyl-acetamide(0.13 mmol) in 9 ml of EtOH is added Pd/C (10%) (65.6 mg) followed by1,4-cyclohexadiene (1.29 mL). The reaction mixture is stirred at roomtemperature for 12 hours and the final product2-{2-[(formyl-hydroxy-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1.4]thiazin-4-yl}-N-propyl-acetamideis obtained by preparative LC/MS using 1 to 99% ACN (in the absence ofTFA) as gradient. MS: (ES⁺): 338.2 [M+1].

Example 72-(7-Chloro-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-N-hydroxy-acetamide

A solution of LDA (2M) (2 mmol) in THF/heptane/ethylbenzene is addeddropwise to a solution of 7-chloro-4H-benzo[1,4]thiazin-3-one (1 mmol)in 2 mL of anhydrous THF kept at 0° C. and under nitrogen. The resultingsolution is stirred at 0° C. for 30 minutes. The reaction mixture iscooled down to −78° C. and then a solution of bromoacetic acid (0.82mmol) in 2 mL of anhydrous THF is added. The stirring is continued for12 hours allowing the temperature to rise to room temperature. Theresulting mixture is diluted with EtOAc and washed with HCl (1M). Theorganic layer is dried over Na₂SO₄, filtered and the solvent evaporated.The crude (7-chloro-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-aceticacid is used in the next step without further purification.

The (7-chloro-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-acetic acidobtained in the previous step is dissolved in 3 mL of Et₂O and EtCOCl(1.2 mmol) is added at 0° C. followed by N-methylmorpholine (1.3 mmol).The reaction mixture is stirred at 0° C. for 10 minutes. Freshlyprepared NH₂OH (1M in MeOH) (1.5 mmol) is added and the reaction stirredat room temperature for 15 minutes. The final2-(7-chloro-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl)-N-hydroxy-acetamideis obtained by preparative LC/MS (in the absence of TFA) using 1 to 99%ACN as gradient. ¹H NMR (400 MHz, MeOD): δ 8.95 (s, 1H), 7.5 (s, 1H),7.3 (d, 1H), 7.05 (d, 1H), 4.35 (s, 2H), 3.6 (s, 2H). MS: (ES⁺): 295.05[M+23].

Example 82-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]thiazin-2-yl)-N-methoxyacetamide

To a solution of (3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-aceticacid (0.21 mmol) in 1 mL of MeOH, K₂CO₃ (0.25 mmol) is added followed byMeI (0.25 mmol). The reaction mixture is stirred at room temperature for12 hours and the final product2-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]thiazin-2-yl)-N-methoxyacetamide isobtained by preparative LC/MS using 10 to 30% ACN as gradient. MS:(ES⁺): 270.05 [M+23].

Example 9 N-Hydroxy-2-(2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetamide

To a solution of 3,4-dihydro-1H-quinolin-2-one (27 mmol) in 250 mL ofanhydrous DMF is added NaH (60% in mineral oil) (30 mmol) and themixture is stirred at room temperature for 30 minutes. 4-Methoxybenzylchloride (30 mmol) is then added and the reaction mixture is stirred atroom temperature for 2 hours. The solvent is evaporated. The residue isdissolved in 100 mL of water and extracted with CH₂Cl₂ three times. Thecombined organic layers are dried over MgSO₄, filtered, and evaporatedto give the crude 1-(4-methoxy-benzyl)-3,4-dihydro-1H-quinolin-2-one,which is used in the next step without further purification. Yield: 95%.

The 1-(4-methoxy-benzyl)-3,4-dihydro-1H-quinolin-2-one (7.86 mmol)obtained in the previous step is dissolved in 10 mL of anhydrous THF. Asolution of freshly prepared LDA (9.43 mmol) in 3.5 mL of anhydrous THFis added dropwise at −78° C. The reaction mixture is stirred at −78° C.for 10 minutes, warmed up to 0° C. for 15 minutes, and then cooled downto −78° C. again before it is transferred dropwise through adouble-ended needle to a solution of tert-butyl bromoacetate (10.2 mmol)in 5 mL of anhydrous THF. The resultant solution is stirred at −78° C.for 1 hour before it is allowed to warm up to 0° C. within another hourand then quenched with MeOH. After removal of the solvent, the residueis purified by silica gel chromatography (hexane/EtOAc) to give[1-(4-methoxy-benzyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-aceticacid tert-butyl ester as a light yellow oil. Yield: 53%. ¹H NMR (400MHz, CDCl₃): δ 7.13 (m, 4H), 6.96 (t, 1H), 6.90 (d, 1H), 6.83 (d, 2H),5.25 (d, 1H), 4.95 (d, 1H), 3.76 (s, 3H), 3.13 (m, 1H), 3.00-2.85 (m,3H), 2.41 (dd, 1H), 1.48 (s, 9H). MS: (ES⁺): 404.2 [M+23].

The [1-(4-methoxy-benzyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-aceticacid tert-butyl ester (3.35 mmol) obtained in the previous step isdissolved in 7 mL of TFA and heated to reflux for 1.5 hours. Afterremoval of the excess TFA under reduced pressure, acid-base extractiongives the crude (2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid asa yellow solid. Yield: 93%.

Following a similar procedure described in example 1, the(2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid obtained in theprevious step is converted into the final N-hydroxy-2-(2-oxo-1,2,34-tetrahydro-quinolin-3-yl)-acetamide. MS: (ES⁺): 243.2 [M+23].

Example 10N-Hydroxy-2-[1-(3-methyl-butyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetamide

(2-Oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid (2.73 mmol), EDCI(3.27 mmol) and DIEA (3.27 mmol) are dissolved in 10 mL MeOH. About 2 mLof CH₂Cl₂ is also added to help dissolving the solid. The reactionmixture is stirred at room temperature for 2 hours before removal of thesolvent under reduced pressure. The residue is purified by silica gelchromatography (hexane/EtOAc) to give(2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester as awhite solid. Yield: 60%. ¹H NMR (400 MHz, CDC1₃): δ 7.88 (br, 1H), 7.18(m, 2H), 7.00 (td, 1H), 6.75 (d, 1H), 3.73 (s, 3H), 3.13-2.98 (m, 3H),2.89 (m, 1H), 2.51 (dd, 1H). MS: (ES⁺): 220.2 [M+1].

Following a similar N-alkylation procedure described in example 9, the(2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester (0.068mmol) obtained in the previous step is alkylated with1-bromo-3-methylbutane to give the crude[1-(3-methyl-butyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acidmethyl ester, which is used in the next step without furtherpurification.

The crude[1-(3-methyl-butyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acidmethyl ester obtained in the previous step is dissolved in 0.5 mL ofanhydrous THF. Freshly prepared NH₂OH (0.77 M in MeOH) (0.44 mL) (alsocontaining 0.77M NaOH) is then added and the mixture is stirred at roomtemperature for 12 hours. The final productN-hydroxy-2-[1-(3-methyl-butyl)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetamideis obtained by preparative LC/MS using 1 to 99% ACN as gradient. ¹H NMR(400 MHz, MeOD): δ 7.29 (t, 1H), 7.20 (d, 1H), 7.11 (d, 1H), 7.04 (t,1H), 3.97 (m, 2H), 3.02-2.89 (m, 2H), 2.77-2.65 (m, 2H), 2.17 (dd, 1H),1.65 (m, 1H), 1.50 (m, 2H), 0.97 (2d, 6H). MS: (ES⁺): 291.3 [M+1].

Example 11N-Hydroxy-2-[2-oxo-1-(pyridin-2-ylcarbamoylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-acetamide

Following a similar N-alkylation procedure described in example 6, the(2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester (0.99mmol) is alkylated with tert-butyl bromoacetate to give(1-tert-butoxycarbonylmethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-aceticacid methyl ester as a colorless oil, after purification by silica gelchromatography (hexane/EtOAc). Yield: 89%. MS: (ES⁺): 356.2 [M+23].

The(1-tert-butoxycarbonylmethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-aceticacid methyl ester (0.30 mmol) obtained in the previous step is dissolvedin 1 mL of CH₂Cl₂/TFA (1:1). The reaction mixture is stirred at roomtemperature overnight before the solvent is removed under reducedpressure. The crude(3-methoxycarbonylmethyl-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-acetic acidis used in the next step without further purification. Yield: 100%.

A solution of(3-methoxycarbonylmethyl-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-acetic acid(0.072 mmol) obtained in the previous step, EDCI (0.087 mmol),2-aminopyridine (0.087 mmol) and DIEA (0.087 mmol) in 0.5 mL of DCM isstirred at room temperature for overnight. After removal of the solvent,the crude[2-oxo-1-(pyridin-2-ylcarbamoylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-aceticacid methyl ester is used in the next step without further purification.

Following a similar procedure described in example 10, the crude[2-oxo-1-(pyridin-2-ylcarbamoylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-aceticacid methyl ester obtained in the previous step is converted to thefinal productN-hydroxy-2-[2-oxo-1-(pyridin-2-ylcarbamoylmethyl)-1,2,3,4-tetrahydro-quinolin-3-yl]-acetamide,which is purified by preparative LC/MS using 1 to 99% ACN as gradient.¹H NMR (400 MHz, MeOD): δ 8.30 (dd, 1H), 8.04 (d, 1H), 7.76 (td, 1H),7.24 (m, 2H), 7.12 (dd, 1H), 7.05 (t, 1H), 6.99 (d, 1H), 4.91 (d, 1H),4.76 (d, 1H), 3.13 (m, 1H), 3.03 (dd, 1H), 2.90 (dd, 1H), 2.73 (dd, 1H),2.25 (dd, 1H). MS: (ES⁺): 355.2 [M+1].

Example 12N-Hydroxy-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-acetamide

NaH (60% in mineral oil) (1.86 mmol) is added to a solution a1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1.55 mmol) in 5 mL of DMF at 0°C., After stirring at 0° C. for 15 minutes, the mixture is allowed towarm up to room temperature. p-Methoxybenzyl chloride (1.94 mmol) isadded to the mixture. After stirring at room temperature for 16 hours,the mixture is poured into 50 mL of water and extracted with EtOAc (3×25mL). The organic layer are combined, washed with brine and dried overMgSO₄. After removing the solvent under reduced pressure, the residue ispurified by flash column chromatography (silica gel) to provide thedesired product1-(4-ethoxy-benzyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as whitesolid. Yield: 90%. MS: (ES⁺): 282.1 [M+1].

A solution of1-(4-methoxy-benzyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.71 mmol)in 2 mL of anhydrous THF is cooled down to −78° C. and freshly preparedLDA (0.85 mmol) is slowly added to the mixture. After the addition, themixture is allowed to warm up to 0° C., then stirred for 30 minutes andcooled down again to −78° C. Tert-butyl bromoacetate (1.0 mmol) isadded. The mixture is stirred at −78° C. for 1 hour and then allowed towarm up to 0° C. To quench the reaction, 1 mL of a mixture of EtOH andwater (1:1) is added to the mixture at 0° C. and the mixture is allowedto warm up to room temperature. Water (20 mL) is added followed byextraction (EtOAc, 3×15 mL). The combined organic layers are washed withbrine and dried over MgSO₄. Solvent is removed under vacuum and theresidue is purified by flash column chromatography (silica gel, 0˜25%EtOAc/hexane) to provide the desired product[1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl]-aceticacid tert-butyl ester as white solid. Yield: 30%. ¹H NMR (400 MHz,CDCl₃): δ 7.24 (m, 2H), 7.13 (m, 4H), 6.75 (d, 2H), 5.10 (d, 1H), 4.80(d, 1H), 2.86(m, 2H), 2.38˜2.50(m, 2H), 2.17(q, 1H), 1.80˜2.05(m, 2H),1.40(s, 9H). MS: (ES⁺): 396 [M+1].

[1-(4-Methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl]-aceticacid tert-butyl ester (0.19 mmol) is dissolved in 1.5 mL of TFA andheated to 100° C. for 3 hours. The mixture is cooled down to roomtemperature and concentrated. The residue is treated with NaOH (1N) (1mL) and extracted with EtOAc (3×1 mL). The aqueous layer is thenneutralized to pH=2 with HCl (1M) and extracted with EtOAc (3×2 mL). Theorganic layers resulted from this extraction is concentrated to providethe crude (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-acetic acid.Yield: 72%.

The (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-acetic acid istreated with EtCOCl and freshly prepared NH₂OH by following a similarprocedure described in example 1 to provide the title compoundN-hydroxy-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-acetamidewhich is purified by preparative LC/MS. ¹H NMR (400 MHz, MeOD) δ 7.28(m, 2H), 7.17(dt, 1H, J=1.2 Hz, J=8.0 Hz), 7.04 (dd, 1H, J=1.2 Hz, J 8.0Hz), 2.90 (m, 2H), 2.72 (m, 1H), 2.55 (m, 1H), 2.28 (m, 1H), 2.15 (m,1H), 1.97 (m, 1H). MS: (ES⁺): 235.3 [M+1].

Example 13N-Hydroxy-N-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylmethyl)-formamide

1-(4-Methoxy-benzyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.71 mmol)synthesized as described in example 12 is dissolved in 5 mL of anhydrousTHF and cooled down to −78° C. A solution of freshly prepared LDA (0.85mmol) is added to the mixture slowly. After stirring at the sametemperature for 10 minutes, the mixture is allowed to warm up to 0° C.for 30 minutes and then cooled down to −78° C. again. Ethyl formate(3.55 mmol) is added dropwise to the reaction mixture. After theaddition, the mixture is stirred at −78° C. for 10 minutes and then thetemperature is risen to 0° C. for 1 hour. The reaction is quenched byaddition of 1 mL of a mixture of water and EtOH (1:1), concentrated anddried under reduced pressure for 24 hours. The residue is redissolved in4 mL of anhydrous THF, Na(AcO)₃BH (2.1 mmol) is added to the mixture andthe resulting mixture is stirred at room temperature for 16 hours. Thereaction mixture is poured into 20 mL of water and extracted with EtOAc(3×10 mL). The organic layers are combined, washed with brine and driedover MgSO₄. Solvent is removed under vacuum and the residue is purifiedby flash column chromatography (silica gel) to provide the desiredproduct3-hydroxymethyl-1-(4-methoxy-benzyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-oneas white solid. Yield: 45%. MS: (ES⁺): 312 [M+1].

To a solution of3-hydroxymethyl-1-(4-methoxy-benzyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one(0.26 mmol) in 2 mL of anhydrous THF at 0° C. is added MsCl (0.39 mmol)and DIEA (0.47 mmol). After the addition, the mixture is allowed to warmup to room temperature and then stirred for 1 hour. The solvent isremoved under vacuum and the residue is treated with water (5 mL) andextracted with EtOAc (3×5 mL). The combined organic layers areconcentrated and the residue is purified by flash column chromatography(silica gel) to provide methanesulfonic acid1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylmethylester as white crystals. Yield: 90%. MS: (ES⁺): 390[M+1].

A mixture of methanesulfonic acid1-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylmethylester (0.15 mmol) in 1 mL of TFA is heated at 80° C. for 3 hours. Thesolvent is removed under vacuum and the residue is treated with neatO-benzylhydroxylamine (0.2 mL) at 100° C. for 16 hours. The reactionmixture is cooled down and directly purified by flash columnchromatography (silica gel, 10˜60% EtOAc/hexane) to provide the crudeproduct3-(benzyloxyamino-methyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as anoil which may still contain small amount of O-benzyl-hydroxylamine. Thecrude product is then added into a mixture of formic acid (1 mL) andacetic anhydride (0.2 mL) at 0° C. and the mixture is stirred at thistemperature for 3 hours. The solvent is removed under reduced pressureand the residue is purified by preparative thin layer chromatography(silica gel, 50% EtOAc/hexane) to provide the desired productN-benzyloxy-N-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylmethyl)-formamideas a white solid. Yield: 36%. MS: (ES⁺): 325 [M+1].

A mixture ofN-benzyloxy-N-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylmethyl)-formamide(0.052 mmol) and Pd/C (10%) (3 mg) in EtOH is degassed and filled withhydrogen. After the mixture is stirred at room temperature for 14 hours,Pd/C is removed by filtration. The filtrate is concentrated and purifiedby preparative thin layer chromatography (10% EtOH/CH₂Cl₂) to providethe title compoundN-hydroxy-N-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylmethyl)-formamide.Yield: 58%. ¹H NMR (400 MHz, MeOD): δ 8.13 (s, 1H), 7.87 (s, 1H), 7.17(m, 2H), 7.06 (t, 1H, J=8.0 Hz), 6.92 (d, 1H, J=8.0 Hz), 3.88 (dd, 1H,J=8.0 Hz, J=14.4 Hz), 3.24 (dd, 1H, J=4.8 Hz, J=14.4 Hz), 2.77 (m, 2H),2.62 (m, 1H), 2.11 (m, 1H), 1.84 (m, 1H). MS: (ES⁺): 235.2 [M+1].

By repeating the procedure described in the above examples, usingappropriate starting materials, the following compounds of Formula I areobtained as identified in Table 1. TABLE 1 Physical Data ¹H NMR 400 MHz(DMSO-d₆) Example Compound and/or MS (m/z) Synthesis 1

332.2 [M + 23]; ¹H NMR (400 MHz, MeOD): δ7.28(m, 1H), 7.18(m, 1H),7.04(m, 1H), 6.96 (m, 1H), 5.26(m, 1H), 3.73(m, 1H), 2.5 (m, 1H),2.19(m, 1H), 1.26 (m, 3H) Described 2

373.20 [M + 1]; ¹H NMR (400 MHz, MeOD) δ 8.23(d, 1H, J=8.0 Hz), 7.90(t,1H, J=8.0 Hz), 7.80(d, 1H, J=8.0 Hz), 7.32(d, 1H, J=9.0 Hz), 7.20(m,2H), 7.05(d, 1H, J=9.0 Hz), 7.01(t, 1H, J=8.0 Hz), 4.77(s, 2H), 3.91 dd,1H, J=6.6 Hz, J=8.8 Hz), 2.65(dd, 1H, J=6.6 Hz, J=14.4 Hz), 2.28(dd, 1H,J=8.8 Hz, J=14.4 Hz). Described 3

317.10 [M + 1]; ¹H NMR (400 MHz, MeOD) δ 7.18(d, 1H, J=8.0 Hz), 6.70(t,1H, J=8.0 Hz), 6.85(d, 1H, J=8.0 Hz), 3.88(dd, 1H, J=9.0 Hz, J=5.6 Hz),2.66(dd, 1H, J=5.6 Hz, J=14.9 Hz), 2.25(dd, 1H, J=9.0 Hz, J=14.9 Hz).Described 4

255.1 [M + 1]; ¹H NMR (400 MHz, MeOD) δ 7.30(dd, 1H, J=1.29 Hz, J=8.0Hz), 7.18, 9dt, 1H, J=1.3 Hz, J=8.0 Hz), 7.01 (dt, 1H, J=1.3 Hz, J=8.0Hz), 6.95(dd, 1H, J=1.3 Hz, J=8.0 Hz), 4.74(d, 1H, J=3.80), 3.97(d, 1H,J=3.8). Described 5

239.1 [M + 1]; ¹H NMR (400 MHz, MeOD): δ8.48(s, 0.4H), 7.97(s, 0.6H),7.39(m, 2H), 7.19(m, 2H), 4.03(m, 2H), 3.5(dd, 1H) Described 6

338.2 [M + 1] Described 7

295.05 [M + 23]; ¹H NMR (400 MHz, MeOD): δ 8.95(s, 1H), 7.5(s, 1H),7.3(d, 1H), 7.05(d, 1H), 4.35(s, 2H), 3.6(s, 2H) Described 8

270.05 [M + 23] Described 9

243.2 [M + 23] Described 10

291.3 [M + 1]; 1H NMR (400 MHz, MeOD): δ7.29(t, 1H). 7.20(d, 1H),7.11(d, 1H), 7.04 (t, 1H), 3.97(m, 2H), 3.02-2.89(m, 2H), 2.77-2.65(m,2H), 2.17 (dd, 1H), 1.65(m, 1H), 1.50(m, 2H), 0.97(2d, 6H). Described 11

355.2 [M + 1]; ¹H NMR (400 MHz, MeOD): δ 8.30(dd, 1H), 8.04(d, 1H),7.76(td, 1H), 7.24 (m, 2H), 7.12(dd, 1H), 7.05(t, 1H), 6.99(d, 1H),4.91(d, 1HH), 4.76 (d, 1H), 3.13(m, 1H), 3.03(dd, 1H), 2.90(dd, 1H),2.73(dd, 1H), 2.25 (dd, 1H). Described 12

235.3 [M + 1]; ¹H NMR(400 MHz, MeOD) δ 7.28(m, 2H), 7.17(dt, 1H, J=1.2Hz, J=8.0 Hz), 7.04(dd, 1H, J=1.2 Hz, J 8.0 Hz), 2.90(m, 2H), 2.72+NL,(m, 1H), 2.55(m, 1H), 2.28(m, 1H), 2.15(m, 1H), 1.97(m, 1H). Described13

235.2 [M + 1]; ¹H NMR (400 MHz, MeOD): δ8.13(s, 1H), 7.87(s, 1H),7.17(m, 2H), 7.06 (t, 1H, J=8.0 Hz), 6.92 (d, 1H, J=8.0 Hz), 3.88 (dd,1H, J=8.0 Hz, J =14.4 Hz), 3.24(dd, 1H, J=4.8 Hz, J=14.4 Hz), 2.77(m,2H), 2.62(m, 1H), 2.11(m, 1H), 1.84 (m, 1H). Described 15

296.2 [M + 1] Synthesized as described for example 1, using bromoacetamide instead of 2- bromo propionamide. 16

278.2 [M + 1] Synthesized as described for example 1, using bromoacetonitrile instead of 2- bromo propionamide. 17

275.0 [M + 23] Synthesized as described for example 1. Using methyliodide instead of 2-bromo- propionamide. 18

315.05 [M + 23] Syntheszied as described for example 1, ussing(bromomethyl)cyclopropane instead of 2-brom- propionamide. 19

333.0 [M + 23] Synthesized as described for example 10, using benzylbromide instead of 1- bromo-3-methylbutane. 20

339.0 [M + 23]; ¹H NMR (400 MHz, DMSO): δ 10.71 (s, 1H), 8.93(s, 1H),7.62 (d, J=2.2 Hz, 1H), 7.344(dd, J=2.2, 8.8, 1H), 6.99(d, J=8.8, 1H),4.41(s, 2H), 3.56 (s, 2H) Synthesized as described for example 3 using7-bromo- 4H-benzo[1,4]thiazin-3- one instead of 7-chloro-4H-benzo[1,4]thiazin-3- one. 21

297.33 [M + 1] Synthesized as described for example 1, using 1-bromo-2-methoxyethane instead of 2-bromo propioamide. 22

335.27 [M + 1] Synthesized as described for example 1, using 3-bromo-1,1,1-trifluoropropane instead of 2-bromo propionamide. 23

309.34 [M + 1] Synthesized as described for example 1, using 1-bromo-3-methylene instead of 2-bromo propionamide. 24

309.2 [M + 1] Synthesized as described for example 1, using 1-bromopentane instead of 2- bromo propionamide. 25

323.2 [M + 1] Synthesized as described for example 1, using 1-bromo-4-methylpentane instead of 2-bromo propionamide. 26

243.15 [M + 23] Synthesized as described in example 7 using 3,4-dihydroquinolin-2(1H)-one as a starting material instead of 7-chloro-4H-benzo[1,4]thiazin-3-one. 27

307.2 [M + 1]; ¹H NMR (400 MHz, CDCl₃): δ 7.38(1H, m), 7.28-7.23(1H, m),7.15-7.13 (1H, m), 7.05-7.013 (1H, m), 4.22-4.17(1H, m); 3.98-3.28(1H,m), 3.85-3.82(1H, m), 2.86-2.784(1H, m), 2.59-2.47(1H, m), 1.93-1.87(2H,m), 1.83-1.69(4H, m) Synthesized as described for example 1, using(bromomethyl)cyclobutane instead of 2-bromo propionamide. 28

371.20 [M + 1] Synthesized as described for example 1, using 2-bromo-1-phenylpropan-1-one instead of 2-bromo propionamide. 29

337.4 [M + 1] Synthesized as described for example 1, using 1-bromo-3,3-dimethylbutan-2-one instead of 2-bromo propionamide. 30

293.3 [M + 1] Synthesized as described for example 1, using 4-bromobut-1-ene instead of 2-bromo propionamide. 31

335.2 [M + 1] Synthesized as described for example 1, using(bromomethyl)cyclohexane instead of 2-bromo propionamide. 32

349.32 [M + 1] Synthesized as described for example 1, using (2-bromoethyl)cyclohexane instead of 2-bromo propionamide. 33

430.10 [M + 23] Synthesized as described for example 2, using 3,4-difluorobenzenamine instead of 2-aminopyridine. 34

428.3 [M + 1]; ¹H NMR (400 MHz, DMSO): δ10.82(s, 1H), 10.37(s, 1H),9.2(bs, 1H), 7.50 (m, 7H), 5.05(dd, 2H), 4.25(m, 1H), 2.9(m, 1H),m2.74(q, 4H), 2.47 (m, 1H), 1.33(t, 6H) Synthesized as described forexample 2, using 2,6- diethylbenzenamine instead of 2-aminopyridine. 35

350.1 [M + 1] Synthesized as described for example 2, usingcyclopentylamine instead of 2-aminopyridine. 36

418.2 [M + 1] Synthesized as described for example 2, using 1-(4-fluorophenyl)ethanamine instead of 2-aminopyridine. 37

275.3 [M + 1]; ¹H NMR (400 MHz, MeOD): δ7.33-7.18(m, 3H), 7.04 (td,J=1.2, 7.2 Hz, 1H), 3.90(m, 2H_), 3.06-2.90 (m, 2H), 2.81-2.65(m, 2H),2.18(dd, J=8.2, 14.8 Hz, 1H), 1.15(m, 1H), 0.55-0.30(m, 4H). Synthesizedas described for example 10, using (bromomethyl)cyclopropane instead of1-bromo-3- methylbutane. 38

422.2 [M + 1] Synthesized as described for example 2, using (2,5-difluorophenyl)methanamine instead of 2- aminopyridine. 40

349.3 [M + 1]; ¹H NMR (400 MHz, MeOD): δ7.29-7.18(m, 2H), 7.06 (t, J=7.2Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 4.59 (m, 2H), 3.42(t, J=6.5 Hz, 2H),3.13(m, 1H), 3.03(dd, J=5.6, 15.6 Hz, 1H), 2.87(dd, J=11.6, 15.4 Hz,1H), 2.66 (m, 3H), 2.43(s, 6H), 2.26(dd, J=8.0, 14.7 Hz, 1H).Synthesized as described for example 11, using N¹,N¹-dimethylethane-1,2-diamine instead of 2-aminopyridine. 41

297.2 [M + 1]; ¹H NMR (400 MHz, MeOD): δ8.26(s, 0.4H), 7.73(s, 0.6H),7.50(m, 1H), 7.33(m, 2H), 7.08(m, 1H), 4.1(m, 1H), 4.08 (m, 1H), 3.90(m,1H), 3.66(m, 1H), 3.62(m, 3H), 3.30(s, 3H) Synthesized in a similar wayas described in example 6, using 1-bromo- 2-methoxyethane instead oftert-butyl bromoacetate. 42

318.15 [M + 23] Synthesized in a similar way as described in example 6,using 2- bromoacetamide instead of tert-butyl bromoacetate. 43

295.2 [M + 1] Synthesized in a similar way as described in example 6,ussing n- butylbromide instead of tert-butyl bromoacetate. 44

293.2 [M + 1] Synthesized in a similar way as described in example 6,using (bromomethyl)cyclopropane instead of tert-butyl bromoacetate. 45

309.2 [M + 1] Synthesized in a similar way as described in example 6,using n- pentylbromide instead of tert-butyl bromoacetate. 46

329.2 [M + 1] Synthesized in a similar way as described in example 6,using benzylbromide instead of tert-butyl bromoacetate. 47

365.0 [M + 23] Synthesized as described for example 1, using 1-(2-bromoethyl)benzene instead of 2-bromo-propionamide. 48

351.2 [M + 23] Synthesized as described for example 1, usingbenzylbromide instead of 2- bromo propionamide. 49

339.2 [M + 1]; ¹H NMR (400 MHz, MeOD): δ7.33(m, 3H), 7.09(m, 1H),4.89(m, 1H), 4.13 (m, 2H), 3.85(m, 5H), 2.7(dd, 1H), 2.31(dd, 1H),1.97(m, 2H) Synthesized as described for example 1, using 2-(2-bromoethyl)-1,3-dioxolane instead of 2-bromo propionamide. 50

337.2 [M + 1] Synthesized as described for example 1, using 2-(bromomethyl))-tetrahydro- 2H-pyran instead of 2- bromo propionamide. 51

253.2 [M + 1]; ¹H NMR (400 MHz, MeOD): δ 7.24(m, 1H), 7.11(m, 1H), 6.91(m, 2H), 3.77(m, 3H), 1.99(s, 3H) Synthesized from 2-(benzyloxyamino-methyl)- 4H-benzo[1,4]thiazin-3-one as described inexample 5 using only Ac₂O. 52

347.2 [M + 1] Synthesized in a similar way as described in example 6,using 1- (bromomethyl)-2- fluorobenzene instead of tert-butylbromoacetate. 53

347.2 [M + 1] Synthesized in a similar way as described in example 6,using 1- (bromoethyl)-4- fluorobenzene instead of tert-butylbromoacetate. 54

365.2 [M + 1] Synthesized in a similar way as described in example 6,using 1- (bromomethyl)-2,4- difluorobenzene instead of tert-butylbromoacetate. 55

354.2 [M + 1] Synthesized in a similar way as described in example 6,using 2- (bromomethyl)benzonitrile instead of tert-butyl bromoacetate.56

354.2 [M + 1] Synthesized in a similar way as described in example 6,using 3- (bromomethyl)benzonitrile instead of tert-butyl bromoacetate.57

354.2 [M + 1] Synthesized in a similar way as described in example 6,using 4- (bromomethyl)benzonitrile instead of tert-butyl bromoacetate.58

359.2 [M + 1] Synthesized in a similar way as described in example 6,using 1- (bromomethyl)-3- meethoxybenzene instead of tert-butylbromoacetate. 59

382.2 [M + 1] Synthesized in a similar way as described in example 6,using 4-(2- bromoacetyl)benzonitrile instead of tert-butyl bromoacetate.60

297.2 [M + 1] Synthesized in a similar way as described in example 6. 61

387.2 [M + 1] Synthesized in a similar way as described in example 6,using methyl-4- (bromomethyl)benzoate instead of tert-butylbromoacetate. 62

373.2 [M + 1] Synthesized in a similar way as described in example 6,using 3- aminopyridine instead of propylamine. 63

349.3 [M + 1] Synthesized in a similar way as described inexample 6,using (2- bromomethyl)cyclohexane instead of tert-butyl bromoacetate. 64

339.2 [M + 1] Synthesized in a similar way as described in example 6,using 2-(2- bromoethyl)-1,3-dioxolane instead of tert-butylbromoacetate. 65

379.3 [M + 1] Synthesized in a similar way as described in example 6,using 1-bromo- 3,7-dimethyloxtane instead of tert-butyl bromoacetate. 66

309.2 [M + 1] Synthesized in a similar way as described in example 6,using 1- bromobutan-2-one instead of tert-butyl bromoacetate. 67

341.2 [M + 1] Synthesized in a similar way as described in example 6,using 1-(2- methoxyethoxy)-2- bromoethane instead of tert-butylbromoacetate. 68

433.3 [M + 1] Synthesized in a similar way as described in example 6,using 3-bromo- 1,1-diphenylpropane instead of tert-butyl bromoacetate.69

267.2 [M + 1] Synthesized in a similar way as described in example 6,using ethylbromide instead of tert-butyl bromoacetate. 70

323.3 [M + 1] Synthesized in a similar way as described in example 6,using 2- ethylbromobutane instead of tert-butyl bromoacetate. 71

299.2 [M + 1] Synthesized in a similar way as described in example 6,using 3- fluoropropane instead of tert-butyl bromoacetate. 72

387.25 [M + 1] Synthesized in a similar way as described in example 6,using 1-((3- bromopropoxy)methyl)benzene instead of tert-butylbromoacetate. 73

387.3 [M + 1] Synthesized in a similar way as described in example 6,using 1-(4- bromobutoxy)benzene instead of tert-butyl bromoacetate. 74

387.2 [M + 1] Synthesized in a similar way as described in example 6,using 2-bromo- 1-(3- methoxyphenyl)ethanone instead of tert-butylbromoacetate. 75

387.2 [M + 1] Synthesized in a similar way as described in examplee 6,using 2-bromo- 1-(4- methoxyphenyl)ethanone instead of tert-butylbromoacetate. 76

373.2 [M + 1] Synthesized in a similar way as described in example 6,using 4- (bromomethyl)benzoic acid instead of tert-butyl bromoacetate.77

412.2 [M + 1] Synthesized in a similar way as described in example 6,using 2-(2- bromoethyl)isoindole-1,3- dione instead of tert-butylbromoacetate. 78

365.3 [M + 1]; ¹H NMR (400 MHz, CDCl₃): δ 7.37(1H, dd, J=1.2 Hz, 7.6Hz), 7.31-7.26(1H, m), 7.14(1H, t, J=7.2 Hz), 7.1-7.04 (1H, m),4.06-3.56(4H, m), 1.62(2H, m), 1.25 (12H, m), 0.87(3H, t, J=6.8 Hz)Synthesized in a similar way as described in example 6, using 3-bromononane instead of tert-butyl bromoacetate. 79

339.2 [M + 1] Synthesized in a similar way as described in example 6,using methyl 4- bromobutanone instead of tert-butyl bromoacetate. 80

320.2 [M + 1] Synthesized in a similar way as described in example 6,using 5- bromopentanenitrile instead of tert-butyl bromoacetate. 81

307.3 [M + 1] Synthesized in a similar way as described in example 6,using 1-bromo- 2-methylprop-1-ene instead of tert-butyl bromoacetate. 82

357.3 [M + 1] Synthesized in a similar way as described in example 6,using 1-(3- bromopropyl)benzene instead of tert-butyl bromoacetate. 83

311.2 [M + 1]; ¹H NMR (400 MHz, CDCl₃): δ7.49(1H, dd, J=8 Hz), 7.36(1H,m), 7.3-7.26 (1H, m), 7.07(1H, t, J=7.6 Hz), 4.24-4.17 (1H, m),4.13-4.032 (1H, m), 3.98-3.93(1H, m), 3.86-3.78(1H, m), 3.77-3.61(3H,m), 3.582-3.48(2H, m), 1.19-1.16(3H, m) Synthesized in a similar way asdescribed in example 6, using 1-bromo- 2-ethoxyethane instead oftert-butyl bromoacetate. 84

321.3 [M + 1]; ¹H NMR (400 MHz, CDCl₃): δ7.37(1H, dd, J=1.2 Hz, 7.6 Hz),7.31-7.26(1H, m), 7.17(1H, t, J=7.2 Hz), 7.08-7.04 (1H, m), 5.08(1H, d,J=5.2 Hz), 4.06-3.55 (5H, m), 2.29(2H, q, J=7.6 Hz), 1.67(3H, s),1.53(3H, s) Synthesized in a similar way as described in example 6,ussing 5-bromo-2-methylpent-2-ene instead of tert-butyl bromoacetate. 85

359.2 [M + 1]; ¹H NMR (400 MHz, CDCl₃): δ 7.56(1H, dd, J=8 Hz),7.39-7.24(4H, m), 7.11-7.07(1H, m), 6.98-6.93(1H, m), 6.87 (2H, dd,J=8.4 Hz, 1.4 Hz), 4.43-4.21 (4H, m), 4.08-3.53(2H, m) Synthesized in asimilar way as described in example 6, using 1-(2- bromoethoxy)benzeneinstead of tert-butyl bromoacetate. 86

353.2 [M + 1] Synthesized in a similar way as described in example 6,using 4- bromobutyl acetate instead of tert-butyl bromoacetate. 87

367.3 [M + 1]; ¹H NMR (400 MHz, CDCl₃): δ 7.43-7.31(3H, m),7.15-7.05(1H, m), 4.12-4.05(4H, m), 3.93-3.77(2H, m), 2.34 (2H, t, J=6.8Hz), 1.69-1.61(4H, m), 1.22(3H, t, J=7.2 Hz) Synthesized in a similarway as described in example 6, using ethyl 5- bromopentanone instead oftert-butyl bromoacetate. 88

323.3 [M + 1]; ¹H NMR (400 MHz, CDCl₃): δ 7.37(1H, dd, J=1.2 Hz, 7.6Hz), 7.31-7.26(1H, m), 7.14(1H, t, J=7.2 Hz), 7.08-7.04 (1H, m),4.06-3.54(4H, m), 1.604(2H, m), 1.29 (6H, m), 0.87(3H, t, J=6.4 Hz)Synthesized in a similar way as described in example 6, using n-bromohexane instead of tert-butyl bromoacetate.

The compounds of the invention, e. g. the compounds of formula I in freeform or in pharmaceutically acceptable salt form or a prodrug thereof,exhibit valuable pharmacological properties, e.g. as anti-infectiousagents, e.g. as indicated by the in vitro test given in Example 3 andare therefore indicated for therapy.

Example 14 Inhibition of Peptide Deformylase Activity

PDF assays with the Saureaus enzyme are performed in duplicate accordingto Clements et al. (Antimicrob. Agents Chemother. 2001, 45, 563-570)using f-Met-Ala-Ser (f-MAS) as substrate and detecting the free aminogroup of the PDF product MAS with fluorescamine. Assays are performed in384 well plates with a final well volume of 50 μl containing 5 nM PDF, 2mM f-MAS, 80 mM HEPES (pH7.4), 0.7M KCl, 1 mM NiCl₂, 0.135% Brij35, and1.25 mM TCEP. The reaction mix is incubated for 30 minutes with variousconcentrations of the inhibitor at room temperature and the free aminogroup of the substrate MAS is detected by the addition of 25 μl of 0.2mg/ml fluorescamine in acetonitrile. Fluorescence is quantified with anAcquest plate reader using an excitation wavelength of 388 nm and anemission wavelength of 445 nm. Assay controls of plus or minus enzymeprovide the 0 and 100% inhibition values, respectively. Analysis of thedata is done by conversion of the fluorescence units to percentinhibition and the data is plotted against percent inhibition. Theconcentration (nanomolar) of inhibitor required to decrease enzymeactivity by 50% (IC50) is determined from a dose response curve.

The compounds of Formula I in free form or in pharmaceuticallyacceptable salt form, exhibit valuable pharmacological properties, e.g.antibacterial properties, for example, as indicated by the in vitrotests of Example 4 and are therefore indicated for therapy. Thecompounds of the invention exhibit inhibitory activity for PDF with anIC₅₀ in the range of 1×10⁻⁹ to 1×10⁻⁵ M, preferably less than 500 nM,more preferably less than 100 nM. For example,N-hydroxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-yl)-acetamide(Example 1) has an IC₅₀ of less than 5 nM.

The compounds of the present invention are, therefore, useful for thetreatment and/or prevention of infectious disorders caused by a varietyof bacterial or prokaryotic organisms.

Examples include, but are not limited to, Gram positive and Gramnegative aerobic and anaerobic bacteria, including: Staphylococci, e.g.S.aureus and S. epidertnidis; Enferococci, e.g. E. faecalis andE.faecium; Streptococci, e.g. S.pneumoniae; Haemophilus, e.g. H.influenza; Moraxella, e.g. M.catarrhalis; Bacteroides, e.g. Bacteroidesfragilis, Clostridium, e.g. Clostridium difficile; Niesseria, e.g.M.meningitides and N.gonorrhoae, Legionella, and Escherichia, e. g.E.coli. Other examples include Mycobacteria, e.g., M tuberculosis;intercellular microbes, e.g. Chlamydia and Rickettsiae; Mycoplasma, e.g.M.pneumoniae; Pseudomonas, e.g. P. aeruginosa; Helecobacter Pylori; andparasites, e.g. Plasmodium falciparum.

As used herein, an “infectious disorder is any disorder characterized bythe presence of a microbial infection, such as the presence of bacteria.Such infectious disorders include, for example, central nervous systeminfections, external ear infections, infections of the middle ear, suchas acute otitis media, infections of the cranial sinuses, eyeinfections, infections of the oral cavity, such as infections of theteeth, gums and mucosa, upper respiratory tract infections, lowerrespiratory tract infections, genitourinary infections, gastrointestinalinfections, gynecological infections, septicemia, bone and jointinfections, skin and skin structure infections, bacterial endocarditis,burns, antibacterial prophylaxis of surgery, antibacterial prophylaxisin immunosuppressed patients, such as patients receiving cancerchemotherapy, or organ transplant patients and chronic diseases causedby infectious organisms, e.g. arteriosclerosis.

The compounds may be used to treat a subject to treat, prevent, and/orreduce the severity of an infection. Subjects include animals, plants,blood products, cultures and surfaces such as those of medical orresearch equipment, such as glass, needles, surgical equipment andtubing, and objects intended for temporary or permanent implantationinto an organism.

Preferred animals include mammals, e.g. mice, rats, cats, dogs, cows,sheep, pigs, horses, swine, primates, such as rhesus monkeys,chimpanzees, gorillas, and most preferably humans. Treating a subjectincludes, but is not limited to, preventing, reducing, and/oreliminating the clinical symptoms caused by an infection of a subject bya microorganism; preventing, reducing, and/or eliminating an infectionof a subject by a microorganism; or preventing, reducing, and/oreliminating contamination of a subject by a microorganism. Themicroorganism involved is preferably a prokaryote, more preferably abacterium.

For the above uses the required dosage will of course vary depending onthe mode of administration, the particular condition to be treated andthe effect desired. The compositions may contain, for example, fromabout 0.1% by weight to about 99% by weight, e. g. from about 10-60% byweight, of the active material, depending on the method ofadministration.

Where the compositions comprise dosage units, each unit will contain,for example, from about 1-1000 mg, e.g. 1-500 mg, of the activeingredient. The dosage as employed for adult human treatment will range,for example, from about 1-3000 mg per day, for instance 1500 mg per daydepending on the route and frequency of administration. Such a dosagecorresponds to about 0.015-50 mg/kg per day. Suitably the dosage is, forexample, from about 5-20 mg/kg per day. Suitable unit dosage forms fororal administration comprise ca. 0.25-1500 mg active ingredient.

The compounds of Formula I can be administered by any conventionalroute, e.g. locally or systemically e.g. orally, topically,parenterally, subdermally or by inhalation and may be used for thetreatment of bacterial infection in a subject such as animals,preferably, mammals, more preferably, humans.

Pharmaceutical compositions comprising a compound of Formula I in freeform or in pharmaceutically acceptable salt form in association with atleast one pharmaceutical acceptable carrier or diluent can bemanufactured in conventional manner by mixing with a pharmaceuticallyacceptable carrier or diluent. A “pharmaceutically acceptable carrier”means an excipient that is useful in preparing a pharmaceuticalcomposition that is generally safe, non-toxic and neither biologicallynor otherwise undesirable, and includes an excipient that is acceptablefor veterinary use as well as human pharmaceutical use. A“pharmaceutically acceptable carriers used in the specification andclaims includes both one and more than one such carriers.

The compounds of the invention may be formulated for administration inany convenient way for use in human or veterinary medicine, by analogywith other antibiotics. Such methods are known in the art (see, e. g.Remington's Pharmaceutical Sciences, Easton, PA: Mack Publishing Co.)and are not described in detail herein.

The compositions may be in any form known in the art, including but notlimited to tablets, capsules, wafers, fast melts (without wafers),powders, granules, lozenges, creams or liquid preparations, such as oralor sterile parenteral solutions or suspensions. The compounds may alsobe administered in liposomal, micellar or emulsion formulations. Thecompounds may also be administered as prodrugs, where the prodrugadministered undergoes biotransformation in the treated mammal to a formthat is biologically active.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, solutions, salves,emulsions, plasters, eye ointments and eye or ear drops, impregnateddressings, transdermal patches, sprays and aerosols, and may containappropriate conventional additives such as preservatives, solvents toassist drug penetration and emollient in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present, for example, from about 1% up to about 99%of the formulation. For example, they may form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example, syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrollidone; fillers, for example, lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example, magnesium stearate, talc, polyethylene glycolor silica; disintegrants, for example, potato starch; or acceptablewetting agents, such as sodium lauryl sulphate. The tablets may becoated according to methods well-know in standard pharmaceuticalpractice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or anothersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example,sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel orhydrogenated edible fats; emulsifying agents, for example, lecithin,sorbitan monooleate or acacia; non-aqueous vehicles (which may includeedible oils), for example, almond oil, oily esters such as glycerine,propylene glycol, or ethyl alcohol; preservatives, for example, methylor propyl p-hydroxybenzoate or sorbic acid, and, if desired,conventional flavoring or coloring agents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, may be eithersuspended or dissolved in the vehicle or other suitable solvent. Inpreparing solutions, the compound may be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampule and sealing. Advantageously, agents such as a local anestheticpreservative and buffering agents may be dissolved in the vehicle. Toenhance the stability, the composition may be frozen after filling intothe vial and the water removed under vacuum. The dry lyophilized powderis then sealed in the vial and an accompanying vial of water forinjection may be supplied to reconstitute the liquid prior to use.Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilization cannot be accomplished by filtration. Thecompound may be sterilized by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the compound.

The compounds of the invention, e. g. the compounds of formula I, may beadministered in free form or in pharmaceutical acceptable salt form e.g. as indicated above. Such salts may be prepared in conventional mannerand exhibit the same order of activity as the free compounds.

In accordance with the foregoing the present invention further provides:

1.1 A method for treating and/or preventing an infectious disorder in asubject, such as a human or other animal subject, comprisingadministering to the subject an effective amount of a compound of theinvention, e. g. of formula I, a pharmaceutically acceptable saltthereof or a prodrug thereof.

1.2 A method for inhibiting peptidyl deformylase in a subject comprisingadministering to the subject an effective peptidyl deformylaseinhibiting amount of a compound of the invention, e. g. of formula I, apharmaceutical acceptable salt thereof or a prodrug thereof.

2. A compound of the invention, e. g. of formula I, in free form or in apharmaceutical acceptable salt form for use as a pharmaceutical, e. g.in any method as indicated under 1.1 or 1.2 above.

3. A pharmaceutical composition, e. g. for use in any of the methods asin 1.1 or 1.2 above comprising a compound of the invention, e. g. offormula I, in free form or pharmaceutical acceptable salt form e. g. inassociation with a pharmaceutically acceptable diluent or carriertherefor.

4. A compound of the invention, e. g. of formula I, a pharmaceuticallyacceptable salt or a prodrug thereof for use as a pharmaceutical or inthe preparation of a pharmaceutical composition for use in any method asindicated under 1.1 or 1.2 above.

“Treating” or “treatment of” a disease includes: (1) preventing thedisease, i.e. causing the clinical symptoms of the disease not todevelop in a subject, e. g. a mammal, that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease, (2) inhibiting the disease, i. e. arresting orreducing the development of the disease or its clinical symptoms, or (3)relieving the disease, i. e. causing regression of the disease or itsclinical symptoms.

“Effective peptidyl deformylase inhibiting amount” means the amount of acompound, a pharmaceutically acceptable salt thereof or a prodrugthereof, that when administered to a subject for treating an infectiousdisorder responsive to inhibition of peptidyl deformylase or forinhibiting peptidyl deformylase, is sufficient to inhibit peptidyldeformylase. The “effective peptidyl deformylase inhibiting amount willvary depending on the compound, salt thereof or prodrug thereof,employed, the microorganism that is inhibited in the subject, the age,weight, sex, medical condition, species, disorder and its severity, ofthe subject to be treated, and the route of administration, but maynevertheless be readily determined by one skilled in the art.

The compounds of the invention, e. g. of formula I, a pharmaceuticallyacceptable salt thereof or prodrug thereof, may be administered alone orin combination with another therapeutic agent. Examples of suchtherapeutic agents include, but are not limited to, other antibacterialagents such as β-lactams, e.g. penicillins; cephalosporins; carbapenems;ketolides; quinolones e.g. fluoroquinolones; macrolides, e.g.clarithromycin, azithromycin or vancomycin; rifamycins; monobactams;isoniazid; licosamides; mupirocin; sulfonamides; phenicols; fosfomycin;glycopeptides; tetracyclines; streptogramins; chloramphenicol; andoxazolidinone, anti-inflammatory agents, e.g. corticosteroids or NSAID,analgesics, e.g. narcotic or non-opioic analgesics.

In accordance with the foregoing the present invention provides in a yetfurther aspect:

5. A method as defined above comprising co-administration, e. g.concomitantly or in sequence, of a therapeutical effective amount of acompound of the invention, e. g. of formula I, a pharmaceuticalacceptable salt thereof or a prodrug thereof, and a second therapeuticagent.

6. A therapeutic combination, e.g. a kit, comprising a) a compound ofthe invention, e.g. of formula I, a pharmaceutically acceptable saltthereof or a prodrug thereof, and b) at least one second therapeuticagent. Component a) and component b) may be used concomitantly or insequence. The kit may comprise instructions for its administration.

The following are representative pharmaceutical formulations containinga compound of formula I.

Tablet Formulation

The following ingredients are mixed intimately and pressed into singlescored tablets: Quantity per Ingredient Tablet (mg) Compound of thisinvention 400 Cornstarch 50 Croscarmalose sodium 25 Lactose 120Magnesium stearate 5

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule: Quantity per Ingredient Capsule (mg)Compound of this invention 200 Lactose, spray--dried 148 Magnesiumstearate 2

Suspension Formulation

The following ingredients are mixed to form a suspension for oraladministration: Ingredient Amount Compound of this invention 1.0 gFumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propylparaben 0.05 g Granulated sugar 25.0 g Sorbitol (70% solution) 13.00 gVeegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5 mgDistilled water q.s. to 100 ml

Injectable Formulation

The following ingredients are mixed to form an injectable formulation:Ingredient Amount Compound of this invention 0.2-20 mg Sodium acetatebuffer solution, .4 M 20 ml HCI (1 N) or NaOH (1 N) q. s. to suitable pHWater (distilled, sterile) q. s. to 20 ml

Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing the compoundof the invention with Witepsol® H-5 (triglycerides of saturatedvegetable fatty acid; Riches-Nelson, Inc., New York), and has thefollowing composition: Compound of the invention  500 mg Witepsol ® 2000mg

The compounds of the invention are useful to inhibit bacteria whereverit is desired to inhibit bacteria by contacting the bacteria with one ormore compounds of the invention. Because of their ability to inhibitbacteria, the compounds of the invention are particularly useful toprevent contamination of cell cultures. As used in this context, theterm “inhibit” means the suppression, control, stasis, or kill ofbacteria.

Eukaryotic cells, in particular animal cells, are often cultured forvarious reasons such as for their ability to produce substances such asproteins. Examples of such cells include Chinese hamster ovary cells(CHO cells), African green monkey kidney cells, hybridomas constructedby fusing a parent cell (myeloma, etc.) with a usefulsubstance-producing normal cell (lymphocyte, etc.), and the like.Typically, the compounds of the invention are incorporated into cellculture media at a bacteria inhibiting amount, e.g., a concentration ofabout 0.0001 to about 10 preferably about 0.0001 to about 1microgram/ml, and more preferably about 0.001 to about 0.1. Anyconventional cell culture medium known in the art can be used.

In accordance with the foregoing the present invention provides in a yetfurther aspect:

7. A method for preventing bacterial contamination of a cell culturemedium comprising incorporating into said cell culture medium a bacteriainhibiting amount of a compound of the invention, e.g. of formula or aacceptable salt thereof.

8. A cell culture medium comprising a bacteria inhibiting amount of acompound of the invention, e.g. of formula or an acceptable saltthereof.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and understanding of this applicationand scope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound of Formula I:

in which: n is 1, 2 or 3; Z is selected from —CH₂—, —CH₂CH₂—, —S—,—S(O)—, —S(O)₂— and —NR₄—; wherein R₄ is selected from hydrogen,hydroxy, halo and C₁₋₄alkyl; R₁ is selected from hydrogen, C₁₋₆alkyl,—XC(O)NR₅OR₆, —XNR₅COR₆ and —XC(O)NR₅R₆; wherein X is selected from abond, C₁₋₆alkylene, C₂₋₆alkenylene and C₂₋₆alkynylene; wherein X can beoptionally substituted with halo, hydroxy and cyano; R₅ is selected fromhydrogen, hydroxy and C₁₋₄alkyl; and R₆ is selected from hydrogen andC₁₋₄alkyl; R₂ is selected from hydrogen, C₁₋₁₂alkyl, C₂₋₁₂alkenyl,C₂₋₁₂alkynyl, halo-substituted-C₁₋₁₂alkyl, —XOR₅, —XOR₇, —XC(O)OR₅,—XOC(O)R₅, —XC(O)NR₅R₆, —XC(O)NR₅R₇, —XC(O)NR₅OR₆, —XR₇, —XCHR₇R₇,—XC(O)R₆, —XOXOR₆, —XOXOR₇, —XC(O)R₇, —XC≡N, —XC(O)XR₇, —XOXR₇,—XC(O)NR₅XR₇ and —XC(O)NR₅XNR₅ ₆; wherein X, R₅ and R₆ are as describedabove and R₇ is selected from C₃₋₁₀cycloalkyl, C₅₋₈heterocycloalkyl,C₆₋₁₀aryl and C₅₋₈heteroaryl; wherein any cycloalkyl, heterocycloalkyl,aryl or heteroaryl of R₇ can be optionally substituted by one to threeradicals selected from halo, C_(1,4)alkyl, C₁₋₄alkoxy, cyano,halo-substituted-C₁₋₄alkyl and —XC(O)OR₅; wherein X and R₅ are asdescribed above; with the proviso that R₁ and R₂ cannot both behydrogen; with the proviso that when R₂ is not hydrogen when R₁ is—CH₂C(O)NHOH; with the proviso that R₁ and R₂ are both not hydrogen; R₃is selected from hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy,halo-substituted-C₁₋₆alkyl and halo-substituted-C₁₋₆alkoxy; and thepharmaceutically acceptable salts, hydrates, solvates, isomers andprodrugs thereof.
 2. The compound of claim I in which: n is 1 or 2; Z isselected from —CH₂—, —CH₂CH₂— and —S—; R₁ is selected from hydrogen,—XC(O)NR₅OR₆ and —XNR₅COR₆; wherein X is selected from a bond,C₁₋₆alkylene, C₂₋₆alkenylene and C₂₋₆alkynylene; wherein X can beoptionally substituted with hydroxy; R₅ is selected from hydrogen,hydroxy and C₁₋₄alkyl; and R₆ is selected from hydrogen and C₁₋₄alkyl;R₂ is selected from hydrogen, C₁₋₁₂alkyl, C₂₋₁₂alkenyl,halo-substituted-C₁₋₁₂alkyl, —XOR₅, —XOR₇, —XC(O)OR₅, —XOC(O)R₅,—XC(O)NR₅R₆, —XC(O)NR₅R₇, —XC(O)NR₅OR₆, —XR₇, —XCHR₇R₇, —XC(O)R₆,—XOXOR₆, —XOXOR₇, —XOXR₇, —XC(O)R₇, —XC≡N, —XC(O)NR₅XR₇ and—XC(O)NR₅XNR₅R₆; wherein X, R₅ and R₆ are as described above and R₇ isselected from C₃₋₁₀cycloalkyl, C₅₋₈heterocycloalkyl, C₆₋₁₀aryl andC₅₋₈heteroaryl; wherein any cycloalkyl, heterocycloalkyl, aryl orheteroaryl of R₇ can be optionally substituted by one to three radicalsselected from halo, C₁₋₄alkyl, C₁₋₄alkoxy, cyano and —XC(O)OR₅; whereinX and R₅ are as described above; R₃ is selected from hydrogen and halo.3. The compound of claim 2 in which n is 1; R₁ is selected fromhydrogen, —XC(O)NR₅OR₆ and —XNR₅COR₆; wherein X is selected from a bond,C₁₋₆alkylene, C₂₋₆alkenylene and C₂₋₆alkynylene; wherein X can beoptionally substituted with hydroxy; R₅ is selected from hydrogen,hydroxy and C₁₋₄alkyl; and R₆ is selected from hydrogen and C₁₋₄alkyl;R₂ is selected from hydrogen, C₁₋₁₂alkyl, C₂₋₁₂alkenyl,halo-substituted-C₁₋₁₂alkyl, —XOR₅, —XOR₇, —XC(O)OR₅, —XOC(O)R₅,—XC(O)NR₅R₆, —XC(O)NR₅R₇, —XC(O)NR₅OR₆, —XR₇, —XCHR₇R₇, —XC(O)R₆,—XOXOR₆, —XOXOR₇, —XOXR₇, —XC(O)R₇, —XC≡N, —XC(O)NR₅XR₇ and—XC(O)NR₅XNR₅R₆; wherein X, R₅ and R₆ are as described above and R₇ isselected from C₃₋₁₀cycloalkyl, C₅₋₈heterocycloalkyl, C₆₋₁₀aryl andC₅₋₈heteroaryl; wherein any cycloalkyl, heterocycloalkyl, aryl orheteroaryl of R₇ can be optionally substituted by one to three radicalsselected from halo, C₁₋₄alkyl, C₁₋₄alkoxy, cyano and —XC(O)OR₅; whereinX and R₅ are as described above; R₃ is selected from hydrogen and halo.4. The compound of claim 3 in which Z is —S—.
 5. The compound of claim 3in which R₁ is selected from hydrogen, methoxy-carbamoyl-methyl,hydroxy-carbamoyl-methyl, hydroxy-carbamoyl-hydroxy-methyl,(formyl-hydroxy-amino)-methyl and (acetyl-hydroxy-amino)-methyl.
 6. Thecompound of claim 3 in which R₂ is selected from hydrogen,carbamoyl-methyl, cyano-methyl, methyl, cyclopropyl-methyl, benzyl,hydroxy-carbamoyl-methyl, 2-methoxy-ethyl, 3,3,3-trifluoro-propyl,3-methyl-butyl, 4-methyl-pentyl, pentyl, cyclobutyl-methyl,1-methyl-2-oxo-2-phenyl-ethyl, cyclohexyl-methyl, cyclohexyl-ethyl,3,3-dimethyl-2-oxo-butyl, but-3-enyl, pyridin-2-yl-carbamoyl-methyl,(3,4-difluoro-phenylcarbamoyl)-methyl,(2,6-diethyl-phenylcarbamoyl)-methyl,[1-(4-fluoro-phenyl)-ethyl-carbamoyl]-methyl,2-oxo-2-pyrrolidin-1-yl-ethyl, (2,5-difluoro-benzylcarbamoyl)-methyl,propyl-carbamoyl-methyl, (2-dimethylamino-ethylcarbamoyl)-methyl, butyl,phenethyl, formyl-hydroxy-amino, 1-carbamoyl-ethyl,2-[1,3]dioxolan-2-yl-ethyl, tetrahydro-pyran-2-yl-methyl,2-fluoro-benzyl, 4-fluoro-benzyl, 2,4-difluoro-benzyl, 2-cyano-benzyl,3-cyano-benzyl, 4-cyano-benzyl, 3-methoxy-benzyl,2-(4-cyano-phenyl)-2-oxo-ethyl, carboxy-methyl,2-(4-carboxy-methyl-ester-phenyl)-2-oxo-ethyl,pyridin-3-yl-carbamoyl-methyl, 3,7-dimethyl-octyl, 2-oxo-butyl,2-(2-methoxy-ethoxy)-ethyl, 3,3-diphenyl-propyl, ethyl, 2-ethyl-butyl,3-fluoro-propyl, 3-benzyloxy-propyl, 4-phenoxy-butyl,2-(3-methoxy-phenyl)-2-oxo-ethyl, 2-(4-methoxy-phenyl)-2-oxo-ethyl,4-carboxy-benzyl, 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl, nonyl,3-methoxy-carbonyl-propyl, 4-cyano-butyl, 3-methyl-but-2-enyl,phenyl-propyl, ethoxy-ethyl, 4-methyl-pent-3-enyl, phenoxy-ethyl,4-methoxycarbonyl-butyl, 4-acetoxy-butyl, 4-propionyloxy-butyl andhexyl.
 7. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 in combination with apharmaceutically acceptable excipient.
 8. A method for treating adisease in an animal in which inhibition of PDF activity can prevent,inhibit or ameliorate the pathology and/or symptomology of the disease,which method comprises administering to the animal a therapeuticallyeffective amount of a compound of claim
 1. 9. The use of a compound ofclaim 1 in the manufacture of a medicament for treating a disease in ananimal in which PDF activity contributes to the pathology and/orsymptomology of the disease.